Chronic inflammatory damage of gastrointestinal mucosa is a hallmark of inflammatory bowel disease (IBD). Commonly known as Crohn's Disease (CD) and Ulcerative Colitis (UC), IBD causes considerable chronic morbidity, including increased risk of malignancies. Aberrant activation of macrophages has been implicated in the pathogenesis of IBD. Nevertheless, the transcriptional control of monocytes to macrophages differentiation and activation remains poorly understood. Such knowledge is crucial for improving management of IBD, which affects more than one million people in the USA. The long-term goal of our study is to understand the mechanisms of monocyte/macrophage development in physiological and pathological conditions. The objective of this proposal is to understand how macrophage terminal differentiation and activation are regulated by VentX and how this mechanism could be utilized to manage IBD. VentX is a recently appreciated hematopoietic homeobox transcriptional factor, whose expression is up-regulated during monocyte-to-macrophage terminal differentiation. Underlying the proposed studies is our central hypothesis: that VentX is a critical regulator of macrophage terminal differentiation and activation in health and disease. Our hypothesis derives from the results of our recent investigation, which showed that VentX promotes and is required for macrophage terminal differentiation and activation. The rationale for the proposed research is that the results of the proposed studies will provide novel mechanistic insight into macrophage terminal differentiation and activation, which is critical for the management of inflammatory bowel diseases. Using combined bioinformatics, biochemical and molecular approaches, the experiments proposed in Aim 1 will focus on the mechanisms of VentX up-regulation during monocyte- to-macrophage terminal differentiation; Aim 2 will define the molecular mechanisms of VentX-controlled monocyte-to-macrophage terminal differentiation; Aim 3 will define the molecular mechanisms underlying VentX-regulated pro-inflammatory activation of intestinal mucosa macrophage; and Aim 4 will explore the role of VentX in clinical management of IBD. On the basis of our identification of VentX as a key regulator of macrophage terminal differentiation and activation, we are uniquely positioned to combine the power of basic and clinical investigations to define the mechanisms of VentX-regulated macrophage differentiation and activation and their potential application in IBD management.